DataSheet1_Examining interactions between polygenic scores and interpersonal trauma exposure on alcohol consumption and use disorder in an ancestrally diverse college cohort.pdf

Introduction: Genetic factors impact alcohol consumption and use disorder (AUD), with large-scale genome-wide association studies (GWAS) identifying numerous associated variants. Aggregate genetic methods in combination with important environmental factors (e.g., interpersonal trauma [IPT]) can be applied to expand our understanding of the ways by which genetic and environmental variables work together to influence alcohol consumption and disordered use. The present study aimed to detail the relationships between genome-wide polygenic scores (PGS) for alcohol phenotypes (i.e., alcohol consumption and AUD status) and IPT exposure as well as the interaction between them across ancestry.
Methods: Data were drawn from the Spit for Science (S4S) study, a US college student population, where participants reported on IPT exposure prior to college and alcohol consumption and problems during college (N = 9,006; ancestry: 21.3% African [AFR], 12.5% Admixed Americas [AMR], 9.6% East Asian [EAS], 48.1% European [EUR], 8.6% South Asian [SAS]). Two trans-ancestry PGS were constructed, one for alcohol consumption and another for AUD, using large-scale GWAS summary statistics from multiple ancestries weighted using PRS-CSx. Regression models were applied to test for the presence of associations between alcohol-PGS and IPT main and interaction effects.
Results: In the meta-analysis across ancestry groups, IPT exposure and PGS were significantly associated with alcohol consumption (βIPT = 0.31, PIPT = 0.0002; βPGS = 0.09, PPGS = 0.004) and AUD (ORIPT = 1.12, PIPT = 3.5 × 10−8; ORPGS = 1.02, PPGS = 0.002). No statistically significant interactions were detected between IPT and sex nor between IPT and PGS. When inspecting ancestry specific results, the alcohol consumption-PGS and AUD-PGS were only statistically significant in the EUR ancestry group (βPGS = 0.09, PPGS = 0.04; ORPGS = 1.02, PPGS = 0.022, respectively).
Discussion: IPT exposure prior to college was strongly associated with alcohol outcomes in this college-age sample, which could be used as a preventative measure to identify students at high risk for problematic alcohol use. Additionally, results add to developing evidence of polygenic score association in meta-analyzed samples, highlighting the importance of continued efforts to increase ancestral representation in genetic studies and inclusive analytic approaches to increase the generalizability of results from genetic association studies.

Introduction: 遗传因素会对酒精摄入与酒精使用障碍（alcohol use disorder, AUD）产生影响，大规模全基因组关联研究（genome-wide association study, GWAS）已识别出诸多相关变异位点。将聚合遗传分析方法与关键环境因素（如人际创伤[interpersonal trauma, IPT]）相结合，可拓展我们对遗传与环境变量共同作用影响酒精摄入与失调性饮酒的机制的认知。本研究旨在阐明酒精相关表型（即酒精摄入与酒精使用障碍患病状态）的全基因组多基因评分（genome-wide polygenic score, PGS）与人际创伤暴露之间的关联，以及二者在不同祖先人群中的交互效应。
Methods: 本研究数据来自“科学唾液（Spit for Science, S4S）”研究队列，该队列纳入美国大学生群体，参与者需报告大学前的人际创伤暴露情况，以及大学期间的酒精摄入与相关问题（总样本量N=9006；祖先构成：21.3%非洲祖先[African [AFR]]、12.5%美洲混血祖先[Admixed Americas [AMR]]、9.6%东亚祖先[East Asian [EAS]]、48.1%欧洲祖先[European [EUR]]、8.6%南亚祖先[South Asian [SAS]]）。研究基于多祖先人群的大规模全基因组关联研究汇总统计量，采用PRS-CSx进行权重校正，构建了两个跨祖先全基因组多基因评分：一个对应酒精摄入，另一个对应酒精使用障碍。采用回归模型检验酒精摄入相关多基因评分与人际创伤的主效应及二者交互效应的显著性。
Results: 在跨祖先人群的元分析中，人际创伤暴露与全基因组多基因评分均与酒精摄入（β_IPT=0.31, P_IPT=0.0002; β_PGS=0.09, P_PGS=0.004）及酒精使用障碍（OR_IPT=1.12, P_IPT=3.5×10^-8; OR_PGS=1.02, P_PGS=0.002）存在显著关联。未检测到人际创伤与性别，亦或人际创伤与多基因评分间存在具有统计学意义的交互效应。对各祖先人群的单独分析结果显示，酒精摄入相关多基因评分与酒精使用障碍相关多基因评分仅在欧洲祖先（EUR）人群中具有统计学意义（分别为β_PGS=0.09, P_PGS=0.04; OR_PGS=1.02, P_PGS=0.022）。
Discussion: 本大学生样本中，大学前的人际创伤暴露与酒精相关结局存在显著关联，该结果可用于识别高风险问题性饮酒的学生，作为预防干预的依据。此外，本研究结果进一步丰富了元分析样本中多基因评分关联的相关证据，强调了持续提升遗传研究中祖先人群代表性的重要性，以及采用包容性分析方法以提升遗传关联研究结果可推广性的必要性。